Glaucoma is a blinding disease affecting millions of people around the world;primary open angle glaucoma (POAG) is the most common form (70-90%). Over 14 POAG loci have been mapped but only 4 of these genes have been identified. Our lab has mapped three of the POAG loci and just recently identified the causative gene for GLC1F. The long-term goal of this proposal is to elucidate how POAG genes cause glaucoma. Our working hypothesis is that each glaucoma locus represents a specific disease entity within the POAG hierarchy and thus, will present with distinct findings, e.g. high intraocular pressure, fast onset of disease or characteristic defects in the optic nerve. In this proposal we seek to identify the genes for the two remaining loci, GLC1C and GLC1G. Our specific aims are: 7 Specific Aim 1. Identify the GLC1G gene and determine the incidence of mutations in POAG populations 7 Specific Aim 2. Identify the GLC1C gene and determine the incidence of mutations in POAG populations. 7 Specific Aim 3. Characterize expression of the GLC1C and GLC1G gene in the anterior segment of the eye, trabecular meshwork cells, and optic nerve of normal and glaucomatous eyes. Completion of these specific aims will increase our knowledge of the genes that cause glaucoma. Potentially either the GLC1C or GLC1G gene may impact a larger proportion of the POAG population than previously identified genes. However, even if they affect only 4-8% of the glaucoma population, identification of these genes will still be of importance because of the pathways that these genes impact. Research into these pathways will lead to a better understanding of what causes glaucoma and ultimately to better treatments based upon this knowledge. PUBLIC HEALTH RELEVANCE: Identification of new glaucoma genes will give insight into what pathways are impacted in glaucoma. This will lead to development of new treatments based upon knowledge of how these pathways function. Better treatments and earlier diagnosis will be based upon a clearer understanding of the clinical phenotypes represented by each locus.